Synopses Borna Disease Virus Infection in Animals and Humans Jürgen A. Richt,* Isolde Pfeuffer,* Matthias Christ,* Knut Frese,† Karl Bechter,‡ and Sibylle Herzog* *Institut für Virologie, Giessen, Germany; †Institut für Veterinär-Pathologie, Giessen, Germany; and ‡Universität Ulm, Günzburg, Germany The geographic distribution and host range of Borna disease (BD), a fatal neuro- logic disease of horses and sheep, are larger than previously thought. The etiologic agent, Borna disease virus (BDV), has been identified as an enveloped nonsegmented negative-strand RNA virus with unique properties of replication. Data indicate a high degree of genetic stability of BDV in its natural host, the horse. Studies in the Lewis rat have shown that BDV replication does not directly influence vital functions; rather, the disease is caused by a virus-induced T-cell–mediated immune reaction. Because antibodies reactive with BDV have been found in the sera of patients with neuro- psychiatric disorders, this review examines the possible link between BDV and such disorders. Seroepidemiologic and cerebrospinal fluid investigations of psychiatric patients suggest a causal role of BDV infection in human psychiatric disorders. In diagnostically unselected psychiatric patients, the distribution of psychiatric disorders was found to be similar in BDV seropositive and seronegative patients. In addition, BDV-seropositive neurologic patients became ill with lymphocytic meningoencephali- tis. In contrast to others, we found no evidence is reported for BDV RNA, BDV antigens, or infectious BDV in peripheral blood cells of psychiatric patients. Borna disease (BD), first described more predilection for the gray matter of the cerebral than 200 years ago in southern Germany as a hemispheres and the brain stem (8,19). In neu- fatal neurologic disease of horses and sheep, owes rons, sometimes in glia cells, acidophilic intra- its name to the town Borna in Saxony, Germany, nuclear inclusion bodies, called Joest-Degen inclu- where a large number of horses died during an sion bodies, are occasionally found. BD occurs epidemic in 1885. The virus etiology of BD was sporadically in Germany and Switzerland; its proven in the early 1900s when Zwick and co- presence in other countries has not yet been workers (1) in Giessen, Germany, successfully substantiated. Natural infections in other Equidae, transmitted brain homogenates from infected ruminants, rabbits, cats, and ostriches have also horses to experimental animals. Other milestones been described (19-21). in BD-related research were the demonstration This review discusses the etiology of Borna of virus growth in cell cultures (2-4); the finding disease, the natural and experimental infection that the pathogenesis of BD is caused by a T-cell– in various animal species, the pathogenesis of dependent immune mechanism (5-8); and most the disease in the experimental rat model, the recently, the molecular characterization of the genetic stability of BDV, and the possible link etiologic agent of BD, the highly neurotropic between BDV or a similar agent and human Borna disease virus (BDV) (9-17). neuropsychiatric disorders. BD is characterized by a disseminated nonpurulent meningoencephalomyelitis with infil- Etiology tration of mononuclear cells (1,8,18,19) and a The etiologic agent of BD, BDV, has been recently characterized as an enveloped, non- Address for correspondence: Jürgen A. Richt, Institut für segmented, negative-stranded RNA virus with a Virologie, Frankfurterstrasse 107, D-35392 Giessen, Germany; genomic size of approximately 9 kb and a nuclear fax: 49-641-99-38359; e-mail: [email protected] giessen.de. site for replication and transcription (14-17). The Vol. 3, No. 3, July–September 1997 343 Emerging Infectious Diseases Synopses genomic organization is similar to that of mem- depression, circular movement, standing in awk- bers of the Mononegavirales order; therefore, ward positions, collapsing, running into obstacles, BDV is the prototype of the new family and paralysis, result from nonpurulent menin- Bornaviridae within this order. The Mono- goencephalomyelitis. Clinical illness usually lasts 1 to negavirales also include Filoviridae (e.g., Marburg 3 weeks, and death rates for diseased horses are and Ebola viruses), Paramyxoviridae (e.g., 80% to 100% (18-20,37). In surviving animals, mumps, measles virus), and Rhabdoviridae (e.g., recurrent episodes are possible, especially after rabies, vesicular stomatitis virus). Six major stress (18). Clinical manifestations, however, may open reading frames (ORFs)(I,II,III, IV,V,x1) are vary among individual animals and various species. predicted in the genome sequence (16,17). Only BD tends to occur in spring and early summer five ORFs correspond to previously identified and is more frequent in some years than in proteins with molecular weights of 10 (ORF x1: others; therefore, arthropods have been discussed p10 BDV gene; 22), 18 (ORF III: gp18 BDV gene; as a potential vector. BDV, however, has never 23), 24 (ORF II: p24 BDV gene; 24), 38/39 (ORF I: been isolated from insects in Europe. In the Near p38 BDV gene; 25), and 94 (ORF IV: p57 BDV East, ticks have been associated with transmission gene; 26) or 84 (ORF IV: p57 BDV gene; 27, Richt of an equine encephalomyelitis similar to BD et al., unpub. obs.) kDa. (38). A definite virus reservoir for BDV has not been found; various rodents most likely represent Natural and Experimental Infection such a reservoir. In addition, since many sero- positive horses with subclinical infections have Natural Infection infectious virus or BDV-specific RNA in various Extensive epizootiologic studies in horses secretions, they can be potential sources of have shown that BD is rare but occurs all over infection for other animals and humans (29,36). Germany, extending beyond the classic disease- endemic regions (28-30). Furthermore, BDV- Experimental Infection specific antibodies were detected in horses in BDV can be experimentally transmitted to a several European countries, Israel (28,29), Japan wide variety of animal species, from chickens to (31), Iran (32), and the United States (33). Since nonhuman primates (1,8,19,20,37). Incubation BDV-specific antibodies are frequently found in periods, clinical signs, and severity of the disease clinically healthy horses (20,28,29), natural infec- depend on the animal species and the virus tions in horses seem to remain subclinical in most variants. Rabbits, Lewis rats, and guinea pigs cases. Unknown exogenous and endogenous fac- are highly susceptible, whereas chickens, tors might influence the genesis of the disease (20). monkeys, cattle, and tree shrews (Tupaia glis;39) In addition to its predominant natural host, are less susceptible (8,19). Some animals (ham- the horse, other Equidae, sheep, cattle, rabbits, sters, black-hooded rats, mice, ferrets, pigeons, goats, deer, alpacas, llamas, cats, pigmy hippo- and dogs), however, do not develop disease potamus, sloth, vari monkeys (memur variegatus), despite being persistently infected with BDV and ostriches have become naturally infected (1,8,18,19). The pathohistologic picture after with BDV (8,19,20,34,35). In sheep flocks, experimental infections resembles that of clinical BD can affect large numbers of animals; natural infections. Most experimentally infected however, in horse stables, usually only a few animals develop perivascular and parenchymal animals show clinical signs. The virus is assumed central nervous system (CNS) infiltrations and to be transmitted through salival, nasal, or have infectious virus in the brain tissue. conjunctival secretions because BDV-specific Frequently, the clinical picture in experimentally RNA has been found in these secretions infected animals does not differ from that of (20,28,29,36). Animals become infected by direct spontaneously infected natural hosts. contact with these secretions or by exposure to The result of BDV infection in rats depends contaminated food or water. A minimum incu- on the inbred rat strain and the virus isolate used bation period of 4 weeks is estimated for horses for infection. Black-hooded rats do not show and sheep with nonspecific signs such as hyper- clinical signs after BDV infection with BDV thermia, anorexia, colic, and constipation in the isolates despite persistent virus infection and initial phase of the disease. During the acute mononuclear infiltration of the CNS (40). Lewis phase of disease, neurologic signs such as ataxia, rats, however, are highly susceptible and are Emerging Infectious Diseases 344 Vol. 3, No. 3, July–September 1997 Synopses therefore used extensively for studies of BD infections in rats depends on the rat strain and the pathogenesis (see below; 5,8,19). When infected passage history of the virus (see above; 19,40). with various BDV variants, Lewis rats exhibited Despite productive virus replication in the clinical manifestations such as behavioral dis- CNS, immunocompromised animals (immuno- orders, paralytic disease, or obesity, in addi- logically incompetent newborn and athymic rats) tion to fertility problems (8,19), which indi- and immunosuppressed (by cyclophosphamide or cates that BDV can form virus variants with cyclosporine A) animals do not become ill with different biologic properties. BD or encephalitis, as do immunocompetent animals (5-8,29,44,46,47). The hypothesis of a Pathogenesis virus-induced cell-mediated immunopathologic BDV is a highly neurotropic agent that gains basis of BD was confirmed in adoptive transfer